The development of an organ or tissue often depends upon a genetic hierarchy of control involving the successive activation of a series of genes. The activity of these genes directs the cellular differentiation events that change a non-specialized cell mass into a mature and functioning organ. Transcription factors are often critical in such developmental pathways. Nuclear receptors are ligand-regulated transcription factors that respond to hormones or other ligands. Orphan receptors are a special sub-class of nuclear receptors that lack known physiological ligands and may have constitutive transcriptional functions. The retinoid-related orphan nuclear receptor b, encoded by the Rorb gene, is specifically expressed in the brain and retina. The expression pattern in retina is suggestive of functions in the differentiation of photoreceptors and other retinal cell types. However, the functions of Rorb in retina remain poorly defined. The study of the Rorb gene therefore offers the opportunity to elucidate novel functions for an orphan nuclear receptor in a defined system, the retina. Progress: 1. The role of Rorb in cone development. In dichromatic mammals, cones express opsin photopigments that are sensitive to short (S, blue) or medium-longer (M, green) wavelengths of light. The mechanisms that differentially regulate M and S opsin expression are critical for color vision but are incompletely understood. Our analysis has indicated that Rorb induces S opsin in cone development. The results suggest that the S opsin gene is directly downstream of Rorb in cone maturation. 2. Ongoing studies suggest that Rorb is also involved in the rod developmental pathway and that these functions are distinct from those in cones. The data suggest that Rorb is multi-functional, having independent roles in different retinal cell populations. 3. The Rorb gene expresses two N-terminal splice variant products. Further studies are investigating how these variant N-terminal products provide additional versatility in directing cell-specific functions in retinal development. Targeted deletions of these Rorb1 and Rorb2 isoforms have been generated in mammalian models and the functional consequences are being determined.